The Clinical Genetics Branch (CGB) integrates molecular and clinical observations in cancer genetics into an interdisciplinary approach involving epidemiologic, clinical, genetic, behavioral, statistical and laboratory methods to define the role of susceptibility genes in cancer etiology. The primary goal of this research program is translate recent dramatic advances in molecular genetics into evidence-based management strategies for persons at increased genetic risk of cancer. The central research strategy relies upon the detailed and meticulous assessment of the individual members of cancer-prone families. [unreadable] [unreadable] Hereditary Breast/Ovarian Cancer (HBOC)[unreadable] [unreadable] Hereditary breast and ovarian cancer (HBOC) is a long-standing DCEG research interest. A major priority remains providing clinical predictive genetic testing for BRCA1/2 mutations to prior participants in CGB research protocols (Protocol 02-C-0212). This involves bringing family members to the Clinical Center for genetic risk assessment, counseling, genetic testing and results disclosure. To date, 157 additional family members have undergone genetic risk assessment; nearly all have chosen genetic testing. Currently, we have 60 hereditary breast/ovarian cancer families under active follow-up. Thirty-five have deleterious mutations in BRCA1 or BRCA2, and two are segregating the CHEK2 variant known as 1100delC. We reported that this rare allele doubles the risk of developing breast cancer in the general population, and likely accounts for a small fraction of BRCA1/2-negative hereditary breast/ovarian cancer families. [unreadable] [unreadable] Thirty-one BRCA mutation-carrying families have been under active follow-up from 5 to 35 years; in this cohort, the prospective risks of breast, ovarian, fallopian tube and peritoneal cancers are being quantified. These families were offered risk-reducing surgery long before BRCA1/2 had been cloned. The first analysis quantified the effect of prophylactic oophorectomy on the prospective risk of breast cancer in BRCA1 mutation carriers. We report a 62% decrease in the risk of breast cancer among women who have undergone prophylactic oophorectomy (in press). Two more manuscripts are now in preparation: (1) quantification of the absolute & relative risks of selected cancers; and (2) description of a novel statistical technique for estimating cumulative cancer risk, accounting for competing risks and delayed cohort entry (under journal review). [unreadable] [unreadable] Our BRCA mutation-negative families comprise a resource for evaluating new candidate high-penetrance breast cancer susceptibility genes. We have reported that two such genes, (ZBRK1 and BRIP1), did not contribute to the risk of breast and ovarian cancer in these families. DNA from these families is being pooled in an international study of genetic modifiers of BRCA1/2 penetrance. This cohort of mutation-positive families was also employed in a recent analysis which did not support prior claims that BRCA1 carriers have a lower ratio of male offspring than do BRCA2 carriers. We have been working to expand our collection of DNA samples from persons known to be either positive or negative for BRCA1/2 mutations, to facilitate studies of genetic modifiers of gene expression. In addition to the above families, we have added 125 mutation-positive families recruited to our Breast Imaging Study, and samples from 1395 participants in GOG 0199, the National Ovarian Cancer Prevention and Early Detection Study. [unreadable] [unreadable] Our study of the prevalence of BRCA1/2 founder mutations in a series of 1000 Ashkenazi Israelis with prostate cancer during 1994 - 1995 documented a two-fold excess of prostate cancer among mutation carriers, supporting the hypothesis that prostate cancer is part of the spectrum of BRCA-related cancers.